Recently, a US National Committee has defined prehypertension individuals as those with persistent blood pressure between 120/80 mm Hg and 139/89 mm Hg. The prehypertension designation identifies people with higher risk of developing hypertension, along with a higher risk for cardiovascular disease. According to the American Heart Association, some 65 million American adults have hypertension and an additional 59 million adults have prehypertension. Hypertension and prehypertension together thus affect more than half of all adults in the US. Many of these individuals are not being treated for their essential hypertension and most of those under treatment with antihypertensive drugs do not reduce blood pressure to the desired level of 115/75 mmHg throughout a 24 hour day. Therefore, there is an unmet need for better antihypertensive treatments.
Normal blood pressure is considered 120/80 mm Hg, but some recent data indicate that 115/75 mm Hg or below is the desired norm. Essential or primary hypertension is defined as a chronic elevation of blood pressure of 140/90 mm Hg or above. Although hypertension seldom produces early symptoms, untreated essential hypertension extending over many years damages the heart and the blood vessels in and between the major organs resulting in increasing risks for aneurysms, arthrosclerosis, heart disease, retinopathy, strokes, and kidney damage.
The environmental and genetic risk factors for hypertension have been extensively studied. The controllable risk factors include: inactivity; excessive alcohol intake; high sodium or saturated fat diet; low potassium, magnesium, or calcium diet; excess weight or obesity; smoking or other CNS stimulants; and high stress. With the growth of fast food restaurants, overeating, decline of aerobic exercise, and hectic lifestyles, the environmental risk factors for hypertension have been increasing in the developed world. The genetic and uncontrollable risk factors for hypertension include: age, race, sex, and family history of diabetes or hypertension. Because the hypertension risk rises greatly after 50 years of age, essential hypertension is expected to increase significantly as the baby boomers reach retirement age. The increasing obesity and diabetes found in the US also raises the risks of hypertension.
The mechanisms underlying essential hypertension are not completely understood, as essential hypertension arises from unidentified causes. Cardiac output increases early in the development of hypertension and then drops as total peripheral resistance of the blood vessels rises. There are at least three theories to explain this rise in peripheral resistance: (1) the inadequate reduction of sodium by the kidneys of some individuals leads to excess water retention; (2) an overactive renin-angiotension system leads to vasoconstriction of blood vessels; and/or (3) an overactive sympathetic nervous system leads to chronic stress.
The treatment of prehypertension or mild hypertension starts with changes in lifestyle to reduce the controllable causes of hypertension such as lack of exercise, smoking, obesity, and poor diet. For those unable to control their hypertension via lifestyle changes, antihypertensive drugs are typically prescribed. Many types of antihypertensive medications are available: angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, diuretics, beta blockers, alpha-blockers, and calcium channel blockers. Which of these drug classes works best for the individual patient is often determined by trial and error. Moreover, doctors often prescribe the use of several classes of antihypertensive drugs simultaneously, as several drugs from different classes are often offer safety and efficacy advantages over higher doses of a single drug class in reaching the desired blood pressure goal.
Refractory or resistant hypertension is somewhat less common than other forms of hypertension. Definitions vary, but hypertension is usually considered refractory if blood pressure cannot be reduced below target levels in patients who are compliant with an optimal drug regimen. In patients with isolated systolic hypertension (ISH), refractoriness has been traditionally defined as a failure of multiple antihypertensive drugs to reduce systolic blood pressure to below 160 mm Hg. As noted above, recent observations strongly indicate that the target level for systolic blood pressure should be no higher than 140 mm Hg.
When blood pressure goals are not attained with standard antihypertensive drug therapy, the first steps are to determine whether the patient does have refractory hypertension and to consider some possible etiologies. The factors include environmental factors; whether the patient adhering to the prescribed regimen; whether pseudoresistance is present; whether drug interactions or adverse reactions may be at fault; whether the patient has a secondary form of hypertension such as renovascular hypertension; whether pressor mechanisms may be responsible for elevating the arterial blood pressure despite antihypertensive drug therapy; and other similar considerations.
When mecamylamine, sold under the tradename Inversine®, was in common use from 1954 to 1960, there were few options to manage blood pressure. When mecamylamine was administered by itself, it initially lowered blood pressure and also decreased renal perfusion. Renal juxtaglomerular (JG) cells responded (due to perceived hypovolemia) by activating the renin-angiotensin axis to restore blood volume and resulting in increased blood pressure. Consequently, clinicians would raise the dose of mecamylamine to counteract this effect. As the dose of mecamylamine was raised, the renin-angiotensin axis was further augmented until, at some point, following continued increasing doses, mecamylamine became poorly tolerated and less effective. At this point concentrations of mecamylamine were well above the EC50 for efficacy and circulating angiotensin 2 and aldosterone concentrations were very high. Twenty to twenty-five years later mecamylamine was no longer used, and ACE inhibitors, which block activation of the renin-angiotensin axis, entered the market.
In treating hypertension with ACE inhibitors or AT2 antagonists alone, the sympathetic system is only partially blocked, often leading to treatment-refractory hypertension. With mecamylamine alone, the renin-angiotensin pathway is activated also commonly producing refractory hypertension. Improved therapies for hypertension are desirable.